Francois Vigneault (Shape Therapeutics)

EX­CLU­SIVE: Shape Ther­a­peu­tics rais­es $112M in bid to make RNA edit­ing — and a whole lot else — a re­al­i­ty

Two years af­ter spin­ning out of CRISPR pi­o­neer Prashant Mali’s lab, Shape Ther­a­peu­tics has a lot more cash and a slight­ly new mis­sion.

The com­pa­ny orig­i­nal­ly launched in 2019 with plans to de­vel­op ther­a­pies around a new form of gene edit­ing, one they hoped could bet­ter ad­dress cer­tain dis­eases than CRISPR or oth­er forms of gene ma­nip­u­la­tions. That’s still their goal, but CEO Fran­cois Vi­gneault has added a few oth­ers in the mean­time.

“The com­pa­ny re­al­ly start­ed as, how can we find a so­lu­tion to some of the lim­i­ta­tions of gene edit­ing?” Vi­gneault said. “But from there, we quick­ly re­al­ized there was a mas­sive bot­tle­neck in an­oth­er sphere of gene ther­a­py.”

Shape end­ed up spend­ing con­sid­er­able time and re­sources try­ing to de­vel­op and make broad­ly avail­able so­lu­tions to two of the biggest con­straints that have held up the broad­er field: man­u­fac­tur­ing and de­liv­ery. They’ll now have a lot more mon­ey to do so and bring for­ward their own med­i­cines, an­nounc­ing a $112 mil­lion Se­ries B on Thurs­day led by Decheng Cap­i­tal and Bre­ton Cap­i­tal.

Shape spe­cial­izes in RNA edit­ing; the com­pa­ny tries to de­vel­op ther­a­pies that in­ter­cept the bro­ken mes­sages that the DNA of pa­tients with cer­tain dis­eases sends out and cor­rect it be­fore it gets turned in­to pro­teins. That con­trasts with CRISPR and oth­er gene edit­ing ap­proach­es that try to di­rect­ly — and per­ma­nent­ly – al­ter DNA.

It does so by ex­ploit­ing a nat­u­ral­ly oc­cur­ring en­zyme that’s al­ready present in hu­man cells called ADAR. By send­ing in their own spe­cial­ly con­struct­ed strand of guide RNA, re­searchers can in the­o­ry re­cruit this en­zyme and get it to ma­nip­u­late spe­cif­ic strands of mes­sen­ger RNA in par­tic­u­lar ways. They could, for ex­am­ple, delete or add bases.

Shape is fo­cus­ing their ef­forts on neu­rons, where ADAR seems to work par­tic­u­lar­ly well — pos­si­bly be­cause it’s nat­u­ral­ly high­ly ex­pressed — and where, by con­trast, CRISPR com­pa­nies have had par­tic­u­lar dif­fi­cul­ty ap­ply­ing their more well-known tech­nol­o­gy. They have lead pro­grams in the rare ge­net­ic dis­ease Rett syn­drome and Parkin­son’s.

In de­vel­op­ing those ther­a­pies, Vi­gneault and his col­leagues ran square in­to the prob­lems every gene ther­a­py com­pa­ny has hit dur­ing the field’s 2010s resur­gence. The vi­ral vec­tors used to shut­tle genes (or in this case, RNA) are dif­fi­cult to man­u­fac­ture at scale. And it’s dif­fi­cult to de­vel­op ones that go pre­cise­ly to the right tis­sue and the right kind of cell in hu­mans.

“We found this [tech­nol­o­gy] is a ma­jor ad­van­tage in neu­rons and CNS dis­or­ders,” Vi­gneault said. “But on the de­liv­ery front what we dis­cov­er is a huge lim­i­ta­tion.”

So Shape en­gi­neered a cell line they claim can pro­duce more ade­no-as­so­ci­at­ed virus (AAV), the most com­mon vi­ral vec­tor used in gene ther­a­py, than any oth­er method. And they in­vest­ed in the tech­nol­o­gy to en­gi­neer AAVs, screen­ing mil­lions of AAVs in cells and mon­keys to de­vel­op ones par­tic­u­lar­ly suit­ed to reach­ing neu­rons or mus­cles.

That puts Shape in di­rect com­pe­ti­tion with com­pa­nies such as Affinia and Dyno, which are ded­i­cat­ed sole­ly to AAV en­gi­neer­ing and have raised hun­dreds of mil­lions of dol­lars and signed bil­lion-dol­lar deals with Big Phar­ma for their vec­tors.

Vi­gneault said Shape will sim­i­lar­ly try to make their AAV and cell lines avail­able to oth­er groups in in­dus­try and acad­e­mia, while con­tin­u­ing to de­vel­op their own ther­a­pies in house and with larg­er com­pa­nies. They have broad am­bi­tions there, too, re­cent­ly up­dat­ing their “pipeline” on­line to show, rather than the few pro­grams clos­est to the clin­ic, a con­stel­la­tion of the dozens of dis­eases they be­lieve their ADAR tech is best suit­ed for, from Alzheimer’s to cys­tic fi­bro­sis.

“The idea is to build a slight­ly dif­fer­ent com­pa­ny than the typ­i­cal one,” Vi­gneault said. “First make a tool that’s dis­rup­tive, not an in­cre­men­tal im­prove­ment, and when you have that tool, make it avail­able so that you can help as many pa­tients as pos­si­ble be­cause one com­pa­ny can’t do it all.”

Cor­rec­tion: The ar­ti­cle has been to clar­i­fy Shape spun out of the Mali lab, not the Church lab.

Biotech Half­time Re­port: Af­ter a bumpy year, is biotech ready to re­bound?

The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

David Livingston (Credit: Michael Sazel for CeMM)

Renowned Dana-Far­ber sci­en­tist, men­tor and bio­phar­ma ad­vi­sor David Liv­ingston has died

David Livingston, the Dana-Farber/Harvard Med scientist who helped shine a light on some of the key molecular drivers of breast and ovarian cancer, died unexpectedly last Sunday.

One of the senior leaders at Dana-Farber during his nearly half century of work there, Livingston was credited with shedding light on the genes that regulate cell growth, with insights into inherited BRCA1 and BRCA2 mutations that helped lay the scientific foundation for targeted therapies and earlier detection that have transformed the field.

No­vo CEO Lars Fruer­gaard Jør­gensen on R&D risk, the deal strat­e­gy and tar­gets for gen­der di­ver­si­ty

 

I kicked off our European R&D summit last week with a conversation involving Novo Nordisk CEO Lars Fruergaard Jørgensen. Novo is aiming to launch a new era of obesity management with a new approval for semaglutide. And Jørgensen had a lot to say about what comes next in R&D, how they manage risk and gender diversity targets at the trendsetting European pharma giant.

John Carroll: I’m here with Lars Jørgensen, the CEO of Novo Nordisk. Lars, it’s been a really interesting year so far with Novo Nordisk, right? You’ve projected a new era of growing sales. You’ve been able to expand on the GLP-1 franchise that was already well established in diabetes now going into obesity. And I think a tremendous number of people are really interested in how that’s working out. You have forecast a growing amount of sales. We don’t know specifically how that might play out. I know a lot of the analysts have different ideas, how those numbers might play out, but that we are in fact embarking on a new era for Novo Nordisk in terms of what the company’s capable of doing and what it’s able to do and what it wants to do. And I wanted to start off by asking you about obesity in particular. Semaglutide has been approved in the United States for obesity. It’s an area of R&D that’s been very troubled for decades. There have been weight loss drugs that have come along. They’ve attracted a lot of attention, but they haven’t actually ever gained traction in the market. My first question is what’s different this time about obesity? What is different about this drug and why do you expect it to work now whereas previous drugs haven’t?

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Raymond Stevens, ShouTi Pharma CEO

A new Schrödinger-backed start­up emerges from the sci­en­tist who mapped the first hu­man GPCR

One of the most popular targets in drug development, representing about a third of existing drugs, are G-protein coupled receptors — the tiny but integral membrane proteins responsible for recognizing things like light, taste, smell, hormones and pain.

But due to challenges in mapping their structure, the protein family remains largely unexplored.

A slate of companies has emerged over the last few years to change that. If one can figure out the structure of these elusive membrane receptors, it might be possible to create small molecule drugs that overcome the limitations of, say, biologic and peptide therapies. That promise is what gets serial entrepreneur Raymond Stevens out of bed in the morning.

Carl June (Brian Ach/Getty Images for TIME 100 Health Summit)

Carl June lends 'wings' to Chi­nese CAR-T start­up led by for­mer post­doc, pur­su­ing off-the-shelf ap­proach with CRISPR fla­vor

Carl June still has plenty of energy to bring forth new iterations of CAR-T technology — wherever they’re coming from.

Adding another role to his already lengthy list of titles, June is joining the scientific advisory board at Nanjing Bioheng Biotech, where he will serve as chairman.

The appointment, if slightly out of the ordinary, is both a testament to the fruitfulness of June’s lab at the University of Pennsylvania and China’s increasing appeal to biotech entrepreneurs educated overseas.

Man­u­fac­tur­ing woes for No­vavax’s Covid jab bad­ly dis­rupt plans for roll­out to the poor — re­port

Production problems at a Novavax facility in Maryland have led to delays in the Covax vaccine sharing program. Now, a shortage of 1 billion doses is expected, as the supplier tries to navigate producing a shot up to regulators’ standards, Politico reported Tuesday.

The company has run into trouble with the purity of the vaccine. Novavax has had trouble proving it can produce a shot consistently up to standards, and it has caused significant delays in the rollout to low- and middle-income countries. This follows several delays at Novavax that has put the executive crew on the defensive.

Sur­geons suc­cess­ful­ly at­tach pig kid­ney to a hu­man for the first time, us­ing tech from Unit­ed's Re­vivi­cor

In a first, researchers reportedly successfully transplanted a pig kidney into a human without triggering an immediate immune response this week. And the technology came from the biotech United Therapeutics.

Surgeons spent three days attaching the kidney to the patient’s blood vessels, but when all was said and done, the kidney appeared to be functioning normally in early testing, Reuters and the New York Times were among those to report. The kidney came from a genetically altered pig developed through United’s Revivicor unit.

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Michel Vounatsos, Biogen CEO (Credit: World Economic Forum/Valeriano Di Domenico)

Break­ing: Bio­gen sells just $300K worth of Aduhelm in Q3, as ques­tions on long-term vi­a­bil­i­ty re­main

Barely anyone is accessing Biogen’s controversial Alzheimer’s treatment, with the company reporting just $0.3 million in Aduhelm sales in the third quarter. Although investors will be looking to the longer term, when CMS may decide to cover the drug and open the floodgates for more reimbursement, use of the drug is currently stalled.

Since June, when the FDA first signed off on the drug under its accelerated pathway, Biogen said Wednesday that it’s sold a total of $2 million worth of Aduhelm. That’s a far cry from the peak Wall Street sales estimate of about $9 billion in annual sales.

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With hun­dreds of mil­lions spent on failed ac­cel­er­at­ed ap­provals, re­searchers call for faster FDA with­drawals

Between 2017 and 2019, Medicare spent more than $220 million on cancer drugs for which the indications were either voluntarily pulled by their applicants or FDA’s oncology adcomm had recommended their withdrawal.

That kind of massive spending on cancer drugs lacking overall survival benefit is wasteful and risks harming people’s health, a research letter published in JAMA Internal Medicine on Monday said. The researchers from Harvard and the London School of Economics called on the FDA to move faster in both requiring timely postmarketing trials and accelerating the speed in pulling these dangling approvals when the confirmatory studies fail.

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